Gianluca Vita

Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes

The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of −15.8 (SD 77.3) m at 12 months, of −58.9 (SD 125.7) m at 24 months and −104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available.

24 Month Longitudinal Data in Ambulant Boys with Duchenne Muscular Dystrophy

Objectives The aim of the study was i) to assess the spectrum of changes over 24 months in ambulant boys affected by Duchenne muscular dystrophy, ii) to establish the difference between the first and the second year results and iii) to identify possible early markers of loss of ambulation. Methods One hundred and thirteen patients (age range 4.1–17, mean 8.2) fulfilled the inclusion criteria, 67 of the 113 were on daily and 40 on intermittent steroids, while 6 were not on steroids. All were assessed using the 6 Minute Walk Test (6MWT), the North Star Ambulatory Assessment (NSAA) and timed test. Results On the 6MWT there was an average overall decline of −22.7 (SD 81.0) in the first year and of −64.7 (SD 123.1) in the second year. On the NSAA the average overall decline was of −1.86 (SD 4.21) in the first year and of −2.98 (SD 5.19) in the second year. Fourteen children lost ambulation, one in the first year and the other 13 in the second year of the study. A distance of at least 330 meters on the 6MWT, or a NSAA score of 18 at baseline reduced significantly the risk of losing ambulation within 2 years. Conclusions These results can be of help at the time of using inclusion criteria for a study in ambulant patients in order to minimize the risk of patients who may lose ambulation within the time of the trial.

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy

The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25years old. A full score was consistently achieved by the age of 5years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials.

Timed rise from floor as a predictor of disease progression in Duchenne muscular dystrophy: An observational study

Background The role of timed items, and more specifically, of the time to rise from the floor, has been reported as an early prognostic factor for disease progression and loss of ambulation. The aim of our study was to investigate the possible effect of the time to rise from the floor test on the changes observed on the 6MWT over 12 months in a cohort of ambulant Duchenne boys. Subjects and methods A total of 487 12-month data points were collected from 215 ambulant Duchenne boys. The age ranged between 5.0 and 20.0 years (mean 8.48 ±2.48 DS). Results The results of the time to rise from the floor at baseline ranged from 1.2 to 29.4 seconds in the boys who could perform the test. 49 patients were unable to perform the test at baseline and 87 at 12 month The 6MWT values ranged from 82 to 567 meters at baseline. 3 patients lost the ability to perform the 6mwt at 12 months. The correlation between time to rise from the floor and 6MWT at baseline was high (r = 0.6, p<0.01). Conclusions Both time to rise from the floor and baseline 6MWT were relevant for predicting 6MWT changes in the group above the age of 7 years, with no interaction between the two measures, as the impact of time to rise from the floor on 6MWT change was similar in the patients below and above 350 m. Our results suggest that, time to rise from the floor can be considered an additional important prognostic factor of 12 month changes on the 6MWT and, more generally, of disease progression.

Diagnosis of Duchenne Muscular Dystrophy in Italy in the last decade: Critical issues and areas for improvements

Despite all the advances in diagnosis and management of Duchenne muscular dystrophy over the past 50 years, the average age at diagnosis in most countries in the world around is still around 4-5 years. This retrospective study investigates the age at diagnosis in Italy in the past 10 years. We report findings from 384 boys who were diagnosed with DMD from 2005 to 2014. The mean age at first medical contact, which raised the suspicion of DMD, was 31 months. The mean age at diagnosis was 41 months. The finding that more frequently brought to suspect a DMD was the incidental finding of consistent elevated creatine kinase serum level detected during routine assessments in children undergoing general anesthesia or with intercurrent illness. This was followed by motor delay and signs of muscle weakness. Initial concerns were raised by general pediatricians (29%), specialists at tertiary centers (35%) or first level hospitals (23%). In children presenting incidental elevated creatine kinase values the diagnosis was achieved earlier than in children presenting a developmental delay. The mean age at diagnosis in our cohort was about 10-12 months lower than that reported in other countries.

Cardiac Function in Types II and III Spinal Muscular Atrophy: Should We Change Standards of Care?

OBJECTIVE In the last years, there has been increasing evidence of cardiac involvement in spinal muscular atrophy (SMA). Autonomic dysfunction has been reported in animal models and in several patients with types I and III SMA, these findings raising the question whether heart rate should be routinely investigated in all SMA patients. The aim of our study was to detect possible signs of autonomic dysfunction and, more generally, of cardiac involvement in types II and III SMA. PATIENTS AND METHODS We retrospectively reviewed 24-hour electrocardiography (ECG) in 157 types II and III SMA patients (age range, 2-74 years). Of them, 82 also had echocardiography. RESULTS None of the patients had signs of bradycardia, atrial fibrillation, or the other previously reported rhythm disturbances regardless of the age at examination or the type of SMA. Echocardiography was also normal. There were no signs of congenital cardiac defects with the exception of one patient with a history of ventricular septal defects. CONCLUSIONS Our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings provide no evidence to support a more accurate cardiac surveillance or changes in the existing standards of care.

Correction: Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes

In the legend for Fig 1, blue and red are accidentally inverted. Please view Fig 1 and the correct caption below. Fig 1 6MWT (left panel) and NSAA (right panel) at baseline, 1, 2 and 3 years in DMD boys, below (blue) and above (red) the age of 7 years. There is an error in the first sentence of the Results section. The correct sentence is: Of the previously reported 113 patients [13] who fulfilled the inclusion criteria and entered the study, 70 also had an assessment at 36 months and another 26 were new patients, enrolled with the same criteria. Of the 43 patients excluded from the second year, 17 had not reached the 3 year assessment, 4 had assessments at different times but not at 3 years because they entered natural history clinical studies, 5 were younger than 5 years at baseline, 9 were lost at follow up and 8 entered into a clinical study. Two of the 5 patients who were excluded because younger than 5 years had also entered a clinical trial.

Parenteral nutrition improves nutritional status, autonomic symptoms and QoL in patients with TTR-FAP

Background Transthyretin related familial amyloidotic polyneuropathy (TTR-FAP) is an inherited form of amyloidosis, leading to death in about 10 years in most cases for cardiac failure or wasting syndrome. Previous study showed that modified body mass index (mBMI) was related to time before death, duration of gastrointestinal disturbances, malabsorption and functional capacity. Futhermore, outcome after liver tranplantation was greater in patients with an mBMI over 600.

T.P.40 Implication of SIRT1 and its downstream pathways in dystrophic process

Abstract Muscle necrosis and exhaustible muscle regeneration are key elements in Duchenne muscular dystrophy (DMD) pathogenesis. Our group has previously highlighted the detrimental effects of the cross-talk between oxidative stress, lipid peroxidation and NF-kappaB/TNF-α activation in the necrotic process in DMD and its murine model. The positive effects of their pharmacological inhibition on muscle regeneration were also demonstrated. Moreover the contribution of telomere shortening to the depletion of regenerative spurt is an emerging field of investigation. SIRT1, an enzyme belonging to the deacetylase family of sirtuins, inhibits NF-kappaB/TNF-α inflammatory pathway. SIRT 1 role in muscle regeneration is still controversial: it promotes telomere maintenance and muscle cell proliferation mediating IGF1 effect. On the other hand, it inhibits mTOR pathway, known to mediate skeletal muscle regeneration and remodeling. This evidence has been provided only by in vitro and in vivo studies and administration of resveratrol, a SIRT 1 activator, ameliorated muscle pathology in mdx mice. This study aimed to investigate the expression of SIRT1, NF-kappaB, IGF1-Akt/PKB and mTOR pathways in dystrophic patient muscles. Muscles of DMD, facioscapulohumeral (FSH) and limb-girdle muscular dystrophies (LGMD) and controls were examined by immunohistochemistry Western blot and real-time PCR. The above mentioned factors have been found overexpressed in DMD and LGMD, at variance with FSH. Moreover SIRT 1 was specifically expressed at immunohistochemistry by miogenin-positive satellite cells. The understanding of the mechanisms controlling SIRT1 and downstream pathways in muscle dystrophies could provide clues in identifying novel therapeutic targets.

D.P.1.12 FSHD and Williams syndrome: The occurrence of two genetic disorders due to heterozygous DNA fragment deletions in the same patient

muscular disorder, is associated with a decreased number of D4Z4 repeats on chromosome 4q35. The pathogenic mechanisms underlying FSHD are still unknown. We report a patient diagnosed with Saethre-Chotzen syndrome at birth. The patient passed four surgeries due to craneosynostosis. High resolution chromosome analyses and molecular biology studies detected a deletion of the gene TWIST1 (SCS) at 7p15-p21. At 9-years old she started walking on tip-toes and subsequently developed facial hypomimia progressive weakness of facial and scapuloperoneal muscles, hyperlordosis and scoliosis. She also presented myopia, isolated focal seizures and moderate mental retardation. CPK levels were increased 2-fold. Muscle biopsy was neurogenic and showed a few angulated atrophic non specific esterase positive denervated fibers and type 2 predominance. Clinical considerations suggested the additional diagnosis of FSHD. Molecular sizing of the tandem D4Z4 repeats at 4q35 showed the presence of a contracted D4Z4 allele having 8 units. To our knowledge, this is the first report of a child with the rare association of SCS and FSHD. The clinical phenotype was essential in order to perform both SCS and FSHD diagnoses.